The long-term goal of this proposal is to define how bacteria modulate their physiology, growth, and development in response to chemical and physical changes in their environment. The project described here utilizes an interdisciplinary and innovative set of genetic, biochemical, biophysical, and computational approaches that will address this question on multiple scales, from the cellular/systems level to the level of molecular structure. The proposed experiments are of biological import, not only to the study of bacterial signal transduction, but cell signaling in general. Results obtained from this project will provide the scientific community with an integrative understanding of bacterial sensory transduction, from signal detection to cellular response. Importantly, as a number of environmental regulatory proteins have been defined as virulence determinants in bacterial pathogens, this work has the potential to inform new therapeutic routes to control certain bacterial infections. Studies will be specifically focused on a multi-protein regulatory system that can function to sense and integrate information about the light environment, chemical and physical stressors, and cellular redox state. This regulatory system will be investigated in the model bacterium, Caulobacter crescentus. However, the genes encoding this system are conserved in a number of bacterial species relevant to human health including the pathogen, Brucella abortus. The specific aims of this project are: 1) Define the mechanism by which LovK-LovR independently controls transcription through two distinct regulatory pathways 2) Characterize the molecular basis of HfiA function as a cell surface adhesin inhibitor. 3) Define the structural basis of PhyR activation by phosphorylation.